Congestive heart failure (CHF) is a clinical syndrome caused by heart disease, characterised by breathlessness and abnormal sodium and water retention, and resulting in oedema. This occurs when the heart is unable to generate a cardiac output sufficient to meet the demands of the body without marked increase of diastolic pressure. It is a consequence of a cardiac disease which impairs ventricular systolic or diastolic function, or both. It is not a single disease but the end stage of many different forms of heart diseases, the most common of which are the coronary artery diseases, hypertension and diabetes (Kannel et al. 1994). Heart failure is manifested by symptoms of poor tissue perfusion (e.g., fatigue, poor exercise tolerance) or congestion of vascular beds (e.g., dyspnoea, pulmonary oedema, peripheral oedema) or both. Treatment of heart failure is generally directed towards its underlying causes.
The prevalence of symptomatic heart failure in the general population in Europe is estimated to be about 0.4-2%. As the prevalence rises rapidly with age, the increasing life expectancy is expected to have a major impact on the incidence of heart failure in the near future. The asymptomatic form of left-ventricular systolic dysfunction is estimated to be as common as symptomatic congestive heart failure (McDonagh et al. 1997).
The current routine clinical and investigative parameters used for the diagnosis of heart failure (clinical examination, electrocardiography, chest X-ray) have been found to be inadequate because the diagnosis causes false-positive results (Remes et al. 1991). Echocardiography provides specific diagnostic and prognostic information, but it is not particularly suitable for screening or for rapid point-of-care diagnostics. Thus, there is a need for new diagnostic tests for cardiac impairment.
A number of studies have demonstrated the usefulness of measurement of single peptides derived from atrial natriuretic peptide prohormone (proANP) and brain natriuretic peptide prohormone (proBNP) in the diagnosis of heart failure (Talwar et al. 2000; De Lemos et al. 2001; Daly et al. 2002). Cardiac impairment is associated with elevated circulating levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), N-terminal fragment of proANP (NT-proANP) and N-terminal fragment of proBNP (NT-proBNP) (Sagnella 1998). High plasma concentrations correlate with poor prognosis after myocardial infarction and heart failure (Omland et al. 2002). Moreover, monitoring plasma levels of NT-proBNP appears to offer more powerful guidance in therapy of heart failure than follow-up by conventional clinical parameters (Troughton et al. 2000).
However prior art diagnostic methods, such as those disclosed in WO 87/06938, WO 00/35951, WO 91/00292, U.S. Pat. No. 5,786,163, EP 648 228 B1, WO 00/45176, WO 00/19207, U.S. Pat. No. 6,124,430, EP 542 255 B1) or those commercially available, are only intended to measure, and are only capable of measuring, a single peptide (ANP, BNP, NT-proANP or NT-proBNP) at a time. For example, the prior art discloses the use of ANP receptor or NPRA (GC-A) receptor in assays to determine natriuretic peptides, but does not disclose any simultaneous determination of natriuretic peptides. U.S. Pat. No. 5,747,274 discloses simultaneous detection of at least three cardiac markers using at least three different monoclonal or polyclonal antibody pairs, each specific for a different marker. Consequently, these assays produce multiple results. Thus there remains in the art a need for a reliable and sensitive but relatively cheap and simple means for detecting or diagnosing cardiac impairment such as heart failure.
Accordingly the present invention provides a test method which detects activation or inactivation of the ANP and BNP hormonal systems by assaying for both proANP- and proBNP-derived peptides simultaneously. Both proANP and proBNP derived peptides may be assayed in the same sample, at the same time. The method produces a single result and is simpler to perform than prior art methods. Moreover the present assay methods show greater sensitivity than prior art methods. Further still, the present test has a profound capability to give a reliable test result whether the patient is in an early phase or late phase of heart failure. The single assay format of the present invention, performed simultaneously per se, offers a cheaper and more cost effective alternative to the available tests thus allowing reliable measurement of activation or inactivation of both the ANP and the BNP hormonal systems